Carrie Y. Inwards

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Operative management of sacral chordoma.

BACKGROUND Sacrococcygeal chordoma presents a difficult diagnostic and therapeutic problem, with a high rate of local recurrence. The purpose of this report is to define the importance of adequate surgical treatment for optimum outcome and survival. METHODS Fifty-two patients underwent surgical treatment for sacrococcygeal chordoma between 1980 and 2001. The series included eighteen female patients and thirty-four male patients, with an average age of fifty-six years (range, thirteen to seventy-six years) at the time of the diagnosis. The surgical approach depended on the level and extent of the lesion, with a posterior approach performed in twenty-two patients and a combined anteroposterior approach used in thirty. A wide surgical margin was achieved in twenty-one patients. RESULTS At an average of 7.8 years (range, 2.1 to twenty-three years) postoperatively, twenty-three patients were alive with no evidence of disease. Twenty-three patients (44%) had local recurrence. The rate of recurrence-free survival was 59% at five years and 46% at ten years. The overall survival rates were 74%, 52%, and 47% at five years, ten years, and fifteen years, respectively. The most important predictor of survival was a wide margin. All patients with a wide margin survived, and this survival rate was significantly different from that for patients who had had either marginal or intralesional excision (p = 0.0001). Of the twenty-one patients with a wide margin, seventeen (81%) had undergone a combined anteroposterior approach and only four had been treated with a posterior approach. CONCLUSIONS A wide surgical margin is the most important predictor of survival and of local recurrence in patients with sacrococcygeal chordoma. Use of a combined anteroposterior approach increases the likelihood of obtaining a wide margin. LEVEL OF EVIDENCE Therapeutic Level IV.

USP6 and CDH11 Oncogenes Identify the Neoplastic Cell in Primary Aneurysmal Bone Cysts and Are Absent in So-Called Secondary Aneurysmal Bone Cysts

Aneurysmal bone cyst (ABC) is a locally recurrent bone lesion that has been regarded as a reactive process. Recently, a neoplastic basis in primary ABC was evidenced by demonstration of clonal chromosome band 17p13 translocations that place the USP6 (TRE2 or TRE17) oncogene under the regulatory influence of the highly active CDH11 promoter. Herein, we report CDH11 and/or USP6 rearrangements in 36 of 52 primary ABCs (69%), of which 10 had CDH11-USP6 fusion, 23 had variant USP6 rearrangements without CDH11 rearrangement, and three had variant CDH11 rearrangements without USP6 rearrangement. USP6 and CDH11 rearrangements were restricted to spindle cells in the ABC and were not found in multinucleated giant cells, inflammatory cells, endothelial cells, or osteoblasts. CDH11 and USP6 rearrangements did not correlate with recurrence-free survival, or with other clinicopathological features. CDH11 and USP6 rearrangements were not found in any of 17 secondary ABC associated with giant cell tumor, chondroblastoma, osteoblastoma, and fibrous dysplasia. These findings demonstrate that primary ABC are mesenchymal neoplasms exhibiting USP6 and/or CDH11 oncogenic rearrangements. By contrast, secondary ABC lack CDH11 and USP6 rearrangements, and although morphological mimics of primary ABC, appear to represent a non-specific morphological pattern of a diverse group of non-ABC neoplasms.

Chondromyxoid fibroma of bone: A clinicopathologic review of 278 cases

In a study of the clinical, radiographic, and pathological features of chondromyxoid fibroma, the tumor was slightly more common in men, usually in the second decade of life. Almost half of the tumors involved the long bones, although the ilium and the small bones were also common sites. Roentgenograms showed a sharply marginated, lobulated, lucent defect in the metaphysis. The tumor involved the medullary bone in an eccentric fashion, and the cortex was thinned and expanded. Periosteal reaction and soft tissue extension were uncommon. Mineralization was identified in 13% of the lesions. Histologically, the tumors were almost always arranged in lobules, which were prominent (macrolobular) or somewhat indistinct (microlobular). The tumor cells were spindle-shaped or stellate and arranged in a myxoid matrix. Calcification was seen in more than one third of the cases but was rarely prominent. Hyaline cartilage and chondroblastoma-like areas were not uncommon. Approximately 18% of tumors showed bizarre nuclei. Permeation of bony trabeculae was uncommon. Treatment was conservative surgical removal; approximately one fourth of the patients had recurrence.

Extradigital glomus tumors: a 20-year experience.

OBJECTIVE To review a large series of extradigital glomus tumors in order to gain a better understanding of their presentation and provide guidelines to aid in their diagnosis and treatment. PATIENTS AND METHODS We performed a retrospective review of all extradigital glomus tumors seen at our institution during a 20-year period (1985-2005) to document the incidence of the classic triad of symptoms, the duration of symptoms, the contribution of imaging to making a definitive diagnosis, and the effectiveness of treatment. RESULTS Fifty-six different patients with extradigital glomus tumors presented as follows: glomus tumors in the hand (3), wrist (4), forearm (11), elbow (4), arm (4), shoulder (2), buttock (1), thigh (5), knee (10), leg (3), ankle (2), foot (2), back (1), nose (1), cheek (1), ear lobe (1), and trachea (1). Forty-eight patients presented with pain and localized tenderness, but only 1 patient presented with cold Intolerance. The average duration of symptoms was greater than 7 years, with most patients being evaluated previously and having their conditions misdiagnosed. Magnetic resonance imaging proved to be the most useful modality for localization of these lesions. Surgical resection was the definitive treatment and generally provided immediate and sustained pain relief. CONCLUSIONS Extradigital glomus tumors are not a rare subgroup of glomus tumors. Treatment outcomes are excellent, but misdiagnosis and delayed diagnosis are common. Improved guidelines regarding symptoms and diagnosis of these neoplasms may reduce the morbidity, ensuing chronic pain, and psychiatric consequences of delayed diagnosis or misdiagnosis.

Desmoplastic fibroma of bone.

Desmoplastic fibroma is a rare primary tumor of bone that histologically and biologically mimics the extra‐abdominal desmoid tumor of soft tissue. This study reviews 27 cases of desmoplastic fibroma, consisting of 9 from the Mayo Clinic files and 18 from our consultation files. There was a male predominance, and 74% of the patients were in the first 3 decades of life. The most frequent sites of involvement were the metaphysis of long bones and the mandible. Radiographically, the tumors were lucent, expansile lesions with well‐defined margins. Histologically, they contained slender spindle cells and various amounts of collagen fibers. En bloc resection is the treatment of choice because a high incidence of recurrence was noticed after lesional curettage.

Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's sarcoma.

Purpose: Tumor markers ideally allow monitoring and prediction of disease progression. In Ewing’s sarcoma, a devastating childhood cancer, only a few reliable prognostic markers have been identified. To this end, we analyzed the expression of four tumor-promoting proteins, cyclin D1, HER2/Neu, Mdm2, and vascular endothelial growth factor (VEGF), in Ewing’s sarcoma. Experimental Design and Results: Thirty-one tissue samples from patients with Ewing’s sarcoma were stained with antibodies against cyclin D1, HER2/Neu, Mdm2, or VEGF. Whereas no significant expression of HER2/Neu and Mdm2 was detected, positive cyclin D1 and VEGF staining was observed in 42% and 55% of all tumors, respectively. Importantly, VEGF expression was found to be an independent negative predictor of survival in Ewing’s sarcoma patients, whereas cyclin D1 expression did not correlate with survival in these patients. Consistently, the Ewing’s sarcoma-specific EWS-ETS oncoproteins were capable of activating both the cyclin D1 and VEGF promoters in transient transfections of tissue culture cells. Furthermore, this activation was enhanced by coexpression of the Sp1 transcription factor. Using a mammalian two-hybrid system, some evidence was obtained that this may involve a physical interaction between EWS-ETS and Sp1 proteins. Conclusions: Our data reveal that VEGF may serve as a prognostic marker in Ewing’s sarcoma patients and provide a molecular mechanism by which VEGF and cyclin D1 expression is up-regulated in approximately half of all Ewing’s sarcomas.

Utility of intraoperative frozen section histopathology in the diagnosis of periprosthetic joint infection: A systematic review and meta-analysis

BACKGROUND The accuracy of intraoperative periprosthetic frozen section histologic evaluation in predicting a diagnosis of periprosthetic joint infection prior to microbiologic culture results is unknown. METHODS We performed a systematic review and meta-analysis of all longitudinal studies that compared frozen section histologic results with simultaneously obtained microbiologic culture at the time of revision total hip or total knee arthroplasty. The data sources were Ovid MEDLINE, Ovid EMBASE, the Cochrane Library, ISI Web of Science, and SCOPUS, from the inception of each database to January 2010. RESULTS Twenty-six studies involving 3269 patients undergoing revision hip or knee arthroplasty met the inclusion criteria. A culture-positive periprosthetic joint infection was confirmed in 796 (24.3%) of the patients. Frozen section results, using any of the diagnostic criteria chosen by the investigating pathologist, had a pooled diagnostic odds ratio of 54.7 (95% confidence interval [CI], 31.2 to 95.7), a likelihood ratio of a positive test of 12.0 (95% CI, 8.4 to 17.2), and a likelihood ratio of a negative test of 0.23 (95% CI, 0.15 to 0.35) for the diagnosis of periprosthetic joint infection. Fifteen studies utilizing a threshold of five polymorphonuclear leukocytes (PMNs) per high-power field to define a positive frozen section had a diagnostic odds ratio of 52.6 (95% CI, 23.7 to 116.2), and six studies utilizing a diagnostic threshold of ten PMNs per high-power field had a diagnostic odds ratio of 69.8 (95% CI, 33.6 to 145.0). There was no significant difference between the diagnostic odds ratio or likelihood ratios associated with these thresholds. The moderate to high heterogeneity among the included studies was unexplained by variability in the study design, diagnostic criteria for acute inflammation, reference standard for periprosthetic joint infection, or prevalence of infection. This heterogeneity could be due to differences in the inclusion and exclusion criteria, tissue sampling error, experience or technique of the pathologists, number of microscopic fields visualized, and field diameter examined. CONCLUSIONS Intraoperative frozen sections of periprosthetic tissues performed well in predicting a diagnosis of culture-positive periprosthetic joint infection but had moderate accuracy in ruling out this diagnosis. Frozen section histopathology should therefore be considered a valuable part of the diagnostic work-up for patients undergoing revision arthroplasty, especially when the potential for infection remains after a thorough preoperative evaluation. The optimum diagnostic threshold (number of PMNs per high-power field) required to distinguish periprosthetic joint infection from aseptic failure could not be discerned from the included studies. There was no significant difference between the diagnostic accuracy of frozen section histopathology utilizing the most common thresholds of five or ten PMNs per high-power field.

Utility of Intraoperative Frozen SectionHistopathology in the Diagnosis ofPeriprosthetic Joint Infection

BACKGROUND The accuracy of intraoperative periprosthetic frozen section histologic evaluation in predicting a diagnosis of periprosthetic joint infection prior to microbiologic culture results is unknown. METHODS We performed a systematic review and meta-analysis of all longitudinal studies that compared frozen section histologic results with simultaneously obtained microbiologic culture at the time of revision total hip or total knee arthroplasty. The data sources were Ovid MEDLINE, Ovid EMBASE, the Cochrane Library, ISI Web of Science, and SCOPUS, from the inception of each database to January 2010. RESULTS Twenty-six studies involving 3269 patients undergoing revision hip or knee arthroplasty met the inclusion criteria. A culture-positive periprosthetic joint infection was confirmed in 796 (24.3%) of the patients. Frozen section results, using any of the diagnostic criteria chosen by the investigating pathologist, had a pooled diagnostic odds ratio of 54.7 (95% confidence interval [CI], 31.2 to 95.7), a likelihood ratio of a positive test of 12.0 (95% CI, 8.4 to 17.2), and a likelihood ratio of a negative test of 0.23 (95% CI, 0.15 to 0.35) for the diagnosis of periprosthetic joint infection. Fifteen studies utilizing a threshold of five polymorphonuclear leukocytes (PMNs) per high-power field to define a positive frozen section had a diagnostic odds ratio of 52.6 (95% CI, 23.7 to 116.2), and six studies utilizing a diagnostic threshold of ten PMNs per high-power field had a diagnostic odds ratio of 69.8 (95% CI, 33.6 to 145.0). There was no significant difference between the diagnostic odds ratio or likelihood ratios associated with these thresholds. The moderate to high heterogeneity among the included studies was unexplained by variability in the study design, diagnostic criteria for acute inflammation, reference standard for periprosthetic joint infection, or prevalence of infection. This heterogeneity could be due to differences in the inclusion and exclusion criteria, tissue sampling error, experience or technique of the pathologists, number of microscopic fields visualized, and field diameter examined. CONCLUSIONS Intraoperative frozen sections of periprosthetic tissues performed well in predicting a diagnosis of culture-positive periprosthetic joint infection but had moderate accuracy in ruling out this diagnosis. Frozen section histopathology should therefore be considered a valuable part of the diagnostic work-up for patients undergoing revision arthroplasty, especially when the potential for infection remains after a thorough preoperative evaluation. The optimum diagnostic threshold (number of PMNs per high-power field) required to distinguish periprosthetic joint infection from aseptic failure could not be discerned from the included studies. There was no significant difference between the diagnostic accuracy of frozen section histopathology utilizing the most common thresholds of five or ten PMNs per high-power field.

Surgical management of conventional grade I chondrosarcoma of long bones.

We retrospectively reviewed 70 patients with low-grade (Grade I) chondrosarcoma of the appendicular skeleton treated at the Mayo Clinic from 1980 to 2001. Fifty-four patients underwent wide resections and three patients underwent marginal excision for radiographically aggressive lesions. Thirteen patients were treated with intralesional curettage for more indolent lesions. The mean age of the patients was 43 years (range, 5-85 years) and the minimum followup was 0.2 year (mean, 8.5 years; range, 0.2-22.8 years). Of the patients who had wide resection, one experienced local recurrence and one had metastasis develop. One patient in the group treated with intralesional curettage had local recurrence and metastasis. We observed no difference in overall survival rate between the intralesional curettage group and the wide resection group. Although there was no difference in the treatment outcome between the two groups, patients with more radiographically aggressive lesions underwent more extensive surgery. The data suggest in selected patients less radiographically aggressive Grade I chondrosarcoma can be safely treated with intralesional curettage without compromising patient outcome.Level of Evidence: Level IV, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.